Résumé
Les conséquences métaboliques de l’obésité sont moins liées à l’augmentation de la masse grasse (MG) qu’à la perte de la flexibilité métabolique du tissu adipeux (TA), qui ne joue plus son rôle de tampon vis-à-vis des flux d’acides gras libres (AGL). La dysfonction du TA évolue en plusieurs étapes: hypertrophie des adipocytes, sécrétion d’adipokines pro-inflammatoires, infiltration par des macrophages puis remodelage fibro-inflammatoire irréversible. L’altération du microenvironnement conduit à une diminution de l’adipogenèse, de même que la sénescence prématurée des préadipocytes. D’un point de vue mécanistique, le concept de capacité d’expansion du TA (expansibilité pour expandability) est séduisant: au-delà d’une certaine limite qui dépend de la taille et du nombre des adipocytes ainsi que de leurs propriétés fonctionnelles, les AGL qui ne peuvent plus être stockés sur place vont constituer des dépôts ectopiques de lipides dans d’autres tissus. L’insulinorésistance de l’obésité est le fait de deux mécanismes majeurs: 1) le dépassement de la capacité d’expansion du TA; 2) la production par le TA de nombreuses adipokines et cytokines pro-inflammatoires qui ont des effets inhibiteurs sur l’action de l’insuline, localement et à distance. Le syndrome métabolique est donc la conséquence de la dysfonction du TA. Les différents sites de TA ont des caractéristiques fonctionnelles variables. Le TA de la partie inférieure du corps apparaît comme protecteur. Le tissu adipeux viscéral (TAV), qui est un marqueur des dépôts ectopiques de lipides, est particulièrement délétère. Les différents phénotypes métaboliques de l’obésité décrivent un continuum de l’obésité androïde banale à la lipodystrophie partielle acquise (excès de TAVet défaut de TA périphérique), habituellement liée à l’âge, mais qui peut apparaître dès l’adolescence. L’obésité apparaît comme une maladie évolutive: croissance précoce et rapide lorsqu’elle commence dans l’enfance et vieillissement accéléré à l’âge adulte. Le phénotype anatomoclinique change avec l’âge et la durée de l’obésité. Sur le plan thérapeutique, le traitement doit être personnalisé pour tenir compte du seuil de MG au-delà duquel apparaissent les complications métaboliques. La prédiction de ce seuil (personal fat threshold) permettrait de tenter de ne pas dépasser cette limite pour éviter les complications métaboliques ou pour les faire régresser, lorsqu’elles apparaissent. En effet, selon des travaux récents, la rémission du diabète de type 2 ou de la stéatohépatite métabolique peut être induite par une perte de poids et de MG importante qui entraîne la disparition des dépôts ectopiques de lipides. De nouvelles stratégies (mode de vie, médicaments, chirurgie bariatrique « ciblée »), qui s’appuieraient sur un phénotypage précis des obésités, méritent d’être développées.
Abstract
The adverse metabolic consequences of obesity are less related to increased fat mass than to impaired metabolic flexibility of adipose tissue (AT), which has a special role in buffering free fatty acids fluxes. The primary signal leading to AT dysfunction is adipocyte hypertrophy leading to insulin resistance, secretion of proinflammatory adipokines, infiltration of macrophages, and finally irreversible fibro-inflammatory remodeling. The decrease of adipogenesis is also a consequence of microenvironment’s alteration as well as of the premature senescence of preadipocytes. From a mechanistic point of view, the AT expandability hypothesis (i.e., the capacity for AT expansion is limited) is attractive: beyond a certain limit, which depends on the size and number of adipocytes and their functional characteristics, excess free fatty acids are orientated to other tissues to form ectopic fat deposition. Obesity-related insulin resistance is the result of two major mechanisms: 1) impaired AT expandability; 2) abnormal AT production of many adipokines and cytokines, which have proinflammatory effects and inhibit insulin action at the local and systemic levels. Metabolic syndrome can be viewed as the result of AT dysfunction. Different AT depot sites have variable functional characteristics. Accumulation of AT in the lower body appears as protector. The visceral AT (VAT), that is, at least a surrogate marker of ectopic fat deposition, is more associated with metabolic disease than overall fat. The different subphenotypes of unhealthy obesity describe a continuum from the common android obesity (central obesity) to the acquired partial lipodystrophic adiposity (excess VAT and loss of peripheral fat), usually related to age, that has been also described in obese children or adolescents. Obesity appears as a progressive disease: early and rapid growth when it begins in childhood and accelerated aging in adulthood. Phenotypes can change as a result of aging or with obesity duration. For a therapeutic perspective, a weight management program has to be personalized to an individual’s threshold of metabolic complications. Prediction of personal fat threshold would help individuals to avoid AT expansion beyond which an overweight individual becomes metabolically unhealthy. There are new evidence that newly diagnosed type 2 diabetes or nonalcoholic steatohepatitis can be reversed by substantial weight and fat loss resulting in decreased ectopic fat deposition. So new strategies (lifestyle, drugs, “targeted” bariatric surgery) that would be based on a more accurate phenoty** of obesity should be developed.
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Ziegler, O., Böhme, P. & Valet, P. De la dysfonction du tissu adipeux blanc aux phénotypes anatomocliniques de l’obésité. Obes 12, 16–41 (2017). https://doi.org/10.1007/s11690-017-0555-z
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DOI: https://doi.org/10.1007/s11690-017-0555-z
Mots clés
- Dysfonction du tissu adipeux
- Expansibilité du tissu adipeux
- Dépôts ectopiques de lipides
- Seuil personnel de masse grasse
- Adiposité lipodystrophique
- Syndrome métabolique